3-Arylthioalkyl-4-optionally substituted sydnones

ABSTRACT

WHEREIN R is hydrogen, lower alkyl, phenyl or bromo, Alk is alkylene having more than 1 and fewer than 5 carbon atoms, x is oxygen, thio, sulfinyl or sulfonyl, x is 0 or 1, and Ar is naphthyl, phenyl or substituted phenyl, preferably having an arylthioalkyl substituent, as typified by 3-(2(phenylthio)ethyl)sydnone, are disclosed.   Preparation and the valuable anti-inflammatory and antibiotic properties of substituted sydnones, represented by the formula

United States Patent Hill May 13, 1975 3-ARYLTHIOALKYL-4-OPTIONALLYPrimary Examiner-Donald G. Daus SUBSTITUTED SYDNONES AssistantExaminer-Raymond V. Rush 75 Inventor: John B. Hill, Northbrook, m. Dhuey[73] Assignee: G. D. Searle & Co., Chicago, ll]. 57 ABSTRACT [22] Filed:Apr. 6,1973 Preparation and the valuable anti-inflammatory andantibiotic properties of substituted sydnones, repre- [21] Appl' 348755sented by the formula Related US. Application Data [63]Continuation-impart of Ser. No. 3|2,708, Dec. 6, u\ l972,aband0ned 9 1;52 11.5. CI 260/307 A; 260/516; 260/518 R; R 260/518 A; 260/519;260/570.55; 260/5706;

260/570]; 424/272 wherein R is hydrogen, lower alkyl, phenyl or bromo.[51] Int. Cl C07d 85/50 Alk is lkylene having more than 1 and fewer than5 [58] Field of Search 260/307 A arb n m x is yg thio, sulfinyl rlfonyl. x is O 01' l, and Ar is naphthyl, phenyl or substituted [56]References Cited phenyl, preferably having an arylthioalkyl substituent,

FOREIGN PATENTS OR APPLICATIONS 5/!959 Germany as typified by3-[2-(phenylthio)ethyl]sydnone. are disclosed.

22 Claims, No Drawings 3-ARYLTHIOALKYL-4-OPTIONALLY SUBSTITUTED SYDNONESThis application is a continuation-in-part of my copending applicationSer. No. 312,708, filed Dec. 6, 1972, now abandoned.

This invention relates to sydnones and to processes for the preparationthereof. More particularly, this invention provides new, useful, andunobvious chemical compounds of the formula git wherein R representshydrogen, halogen, lower alkyl, (lower alkoxy)carbonyl(lower alkyl),carboxy(lower alkyl), cycloalkyl, phenethyl, benzyl, or phenyl; Alk' andAlk" each represent lower alkylene; X represents oxygen, optionallyalkylated imino, optionally alkylated phosphinidene, oroptionally-oxygenated sulfur; 1: represents or l; and Ar representsphenyl, naphthyl, anthryl, phenanthryl (each of which can be substitutedby lower alkyl, halogen amino, carboxyl, lower alkoxy, and/or nitro),pyridyl, pyrimidyl, quinolyl, isoquinolyl, pyrrolyl, thienyl, fury],imidazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzoxazolyl or benzothiazolyl.

The halogens comprehended by R and (as substituents in the aromaticnucleus contemplated) Ar are fluoro, chloro, bromo, and iodo, amongwhich, in the case of R but not Ar, bromo is preferred.

The lower alkyls comprehended by R and Ar are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec. butyl, tert.-butyl, pentyl, neopentyl,hexyl, isohexyl, heptyl and like monovalent, saturated, acyclic,straightor branched-chain, hydrocarbon groupings of the formula whereinn represents a positive integer less than 8.

The cycloalkyls contemplated by R are preferably those containing morethan 2 and fewer than 7 carbons, viz., cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexvl.

The lower alkylenes contemplated by Alk' and Alk" are methylene,ethylene, trimethylene, propylene, tetramethylene, l,l-dimethylethylene,pentamethylene, 2,2-dimethyltrimethylene, and like bivalent, saturatedacyclic, straightor branched-chain, hydrocarbon groupings having theformula wherein n is defined as before. Among these lower alkylenes,those containing more than 1 and fewer than carbon atoms are preferredembodiments of Alk'; and methylene is the preferred embodiment of Alk".

The optionally-oxygenated sulfur contemplated by X is thio, sulfinyl, orsulfonyl, any of which is presently, but not necessarily ultimately,preferable to oxygen.

The optionally alkylated imino and phosphinidene groupings arerepresented, respectively, by

and -P- wherein R is hydrogen or straightor branched-chain alkylcontaining 1 to 7 carbon atoms inclusive.

The lower alkoxys contemplated by R and Ar are groupings of the formulalower alkylO wherein lower alkyl is defined as above.

The point of attachment of the groups contemplated by Ar is notcritical; and the positioning of the optional substituents therein(viz., lower alkyl, halogen, lower alkoxy, and/or nitro) relative to thepoint of attachment of the phenyl, naphthyl, anthryl or phenanthrylnucleus and alsowhere more than I is present-relative to each other, isnot critical. Although more than 1 such substituent can be present,alike or different, fewer than 4 halogens or fewer thahn 2 of the othersubstituents is preferred.

The compounds to which this invention relates are useful by reason oftheir valuable biological properties. An especially valuable propertycharacteristic of the instant compounds is anti-inflammatory activity.The compounds are also antibiotic, being effective against bacteria suchas Bacillus subrilis and Erwinia sp., fungi such as Trichophytonmenlagrophytes and Verlicillium alho-atrum, and algae such as Chlorellavulgaris.

The anti-inflammatory utility of the instant compounds is evident fromthe results of a standardized test for this property described in theparagraph beginning with line 34 in column 2 of US. Pat. No. 3,528,966.

Further evidence of the anti-inflammatory utility of the instantcompounds is provided by the results of a standardized test for theircapacity to inhibit the edema induced in rats by injection ofcarrageenin. The procedure is a modification of one described by Winter,et al., Proc. Soc. Exp. Biol. Med., ll 1, S44 (1962). Corn pound isadministered subcutaneously or intragastrically-dissolved or suspendedin 0.5 ml. of aqueous 0.85% sodium chloride, propylene glycol, a mixtureof these vehicles, or corn oilto each of 10 male rats weighing l00l30gm. A like group of rats to which is identically and concurrentlyadministered vehicle alone serves as controls. Precisely l hour later,each animal is injected under the plantar surface of each hind foot with0.l ml. of an aqueous 1% solution of carrageenin (Marine Colloids, lnc.,Type 402). A compound is considered antiinflammatory if the averagetotal volume of the 2 hind feet in the group treated therewith, which ismeasured in arbitrary units 5 hr. after the carrageenin injection, issignificantly (P 4 0.05) less than the corresponding value for thecontrol group.

Still further evidence of the anti-inflammatory utility of the instantcompounds is provided by the results of a standardized test for theircapacity to inhibit the edema induced in rats by injection ofMycobacterium butyricum. The procedure, which is similar to onedescribed by Pearson, et al., Arthritis Rheumat., 2, 440 (1959),follows. Intact male Sprague-Dawley rats are randomized in groups of l2,1 group for each compound to be tested plus 1 group to serve ascontrols. Each animal is injected intradermally (without any anesthesia)on the base of the tail with 0.6 mg. of dry heat-killed Mycobac'teriumbulyricum (Dzfcu 0640-33) suspended in 0.05 ml. of paraffin oilcontaining 2% digitonin, whereupon the prescribed dose of compound(initially 5 mg.)-dissolved or suspended in a vehicle consisting of 0.2ml. of either corn oil or a mixture of 20 ml. of aqueous 0.85% sodiumchloride with I drop of polysorbate 80is intragastrically orsubcutaneously administered. Administration thus of compound is repeateddaily for the next l8 consecutive days. The control group is identicallyand concurrently adminis tered vehicle alone. On the 20th day, the ratsare sacrificed, and the total volume of each pair of hind feet ismeasured in arbitrary units. A compound is considered anti-inflammatoryif the average volume of the hind feet in the group treated therewith issignificantly (P 0.05) less than the corresponding value for the control group The product of Example lD hereinafter was found to beanti-inflammatory at l mg, intragastrically in the first and third ofthe foregoing three tests, and at 10 mg. subcutaneously in the remainingtest.

The antibiotic utility of the instant compounds can be demonstrated bystandardized tests described in US. Pat. No. 3,682,951, as follows: forantibacterial activity, see line 44, column 2, through line 5, column 3;for antifungal and anti-algal activities, see line 62, column 3, throughline 64, column 4.

Those skilled in the art will recognize that observations of activity instandardized tests for particular biological effects are fundamental tothe development of valuable new drugs, both veterinary and human.Distinct from such applications, anti-algal compounds are adapted to theconditioning of boiler feedwater and the like.

Preparation of the compounds of this invention proceeds by heating anamine of the formula with a 2-bromoalkanoic acid of the formula ll l Br-C l lC OOH in the presence of sodium methoxide, using tert/-butylalcohol as solvent. In the foregoing 2 formulas, Alk', Alk", .r, and Arretain the meanings previously assigned; R' is identical with R exceptthat halogen is exeluded; and X represents oxygen, thio, optionallyalkylated imino or optionally alkylated phosphinidene, Potassiumcarbonate or sodium hydroxide can be substituted for the sodiummethoxide, and tetrahydrofuran or ethyl alcohol for the tert.-butylalcohol, if desired. The resultant amino acid is converted to thecorresponding N-nitroso compound by contacting for 4'15 hr. at ()5C.with sodium nitrite and hydrochloric acid in a solvent medium comprisingwater and dichloromethane. Prolonged reaction times. higher reactiontemperatures, excess sodium ni trite, and/or substitution of acetic forhydrochloric acid may promote oxidation of thio, if present, tosulfinyl, From an N-nitrosoamino acid of the formula in which X"represents oxygen, optionally alkylated imino, optionally alkylatedphosphinidene, thio, or sulfinyl and R, Alk'. Alk", x, and Ar aredefined as before, upon prolonged contact with acetic anhydride in anitrogen atmosphere, the corresponding sydnone R N-Alk-X"(Alk" -Ar isobtained. The sulfidic sydnones ofthis invention, i.e., those having theformula which is accomplished by contacting the corresponding4-unsubstituted sydnones, in the presence of potassium acetate, withhalogen and acetic acid.

The amines offormula i when Alk' is ethylene can be prepared by treatinga compound of the formula with azacyclopropane. Alternatively, but notlimited to the situation when Alk is ethylene, the amines of for mula Ican be prepared by treating a compound of the formula Ar(Alk"),XH

with a primary amine of the formula Br- Alk'-NH using alcohol solventssuch as methanol. ethanol and t-butanol. In the above formulas Ar, Alk',Alk", x and X remain as defined hereinbefore.

The following examples describe in detail compounds illustrative of thepresent invention and methods which have been devised for theirpreparation. It will be apparent to those skilled in the art that manymodifications, both of materials and of methods, may be practicedwithout departing from the purpose and intent of this disclosure.Throughout the examples hereinafter set forth, temperatures are given indegrees Centigrade and relative amounts of materials in parts by weight,except as otherwise noted.

EXAMPLE l A. N-[Z-(Phenylthio)ethyllglycinonitrile hydrochloride. Amixture of 37 parts of 2-(phenylthio)ethylamine, 12 parts of sodiumcyanide, 22 parts of 30% formalin, and 24 parts of concentratedhydrochloric acid in l25 parts of water is stirred for 3 hours, thendiluted with 450 parts of benzene. The resultant mixture is washed withwater and thereupon extracted with saturated aqueous sodium bicarbonate.The extract is neutralized with concentrated hydrochloric acid, and theresultant mixture is extracted with benzene. The benzene extract isstripped of solvent by vacuum distillation, and the oily residue istaken up in methyl alcohol. Just sufficient hydrogen chloride dissolvedin isopropyl alcohol to induce acidity is added, and the resultantprecipitate is filtered off and dried in air. The product thus isolatedis N-[2-(phenylthio)ethyl1glycinonitrile hydrochloride melting atapproximately l25-l 26'.

B. Barium N-[2 (phenylthio)ethyl]glycinate. A mixture of 3l parts ofN-[2-(phenylthio)ethyl]glycinonitrile hydrochloride, 86 parts of bariumhydroxide, 360 parts of water, and approximately 350 parts of methylalcohol is heated t the boiling point under reflux for 5 hours, thencooled and filtered. The insoluble solid thus isolated is bariumN-[2-(phenylthio)ethyl]glycinate which, when recrystallized from water,melts at l93-l96.

C. N-Nitroso-N-[2-(phenylthio)ethyl]glycine. A mixture of 40 parts ofbarium N-[2-(phenylthio)ethyl]- glycinate, l4 parts of sodium nitrite,280 parts of water, and 107 parts of dichloromethane is stirred at 0 for2 hours, whereupon l4 parts of concentrated hydrochloric acid isintroduced. A further 14 parts of sodium nitrite is then addedportionwise with stirring during 4 hours at 0, after which stirring iscontinued at 0-5 for IS hours. The resultant mixture is filtered, thefiltrate is extracted with dichloromethane, and the extract is washedwith water and then extracted in turn with saturated aqueous sodiumbicarbonate. The bicarbonate extract is acidified with concentratedhydrochloric acid, and the resultant mixture is extracted withdichloromethane. Evaporation of solvent affords N-nitroso-N[2-(phenylthio)ethyl1glycine as the residue.

D. 3-[2-(Phenylthio)ethyl]sydnone. A mixture of 8 parts ofN-nitroso-N-[Z-(phenylthio)ethyl]glycine and I08 parts of aceticanhydride is maintained at room temperatures under nitrogen for 4 days,then poured into 500 parts of water. The resultant mixture is stirredfor 2 hours at room temperatures, then extracted with dichloro-methane.The dichloromethane extract is consecutively washed with water,saturated aqueous sodium bicarbonate, and water, then stripped ofsolvent by vacuum distillation. The residue is3-[2-(phenylthio)ethyl]sydnone which, recrystallized from ether, meltsat 40-42. The product has thc formula EXAMPLE 2 A.N-[2-(p-Chlorophenylthio)ethyl]glycine. A mixture of 38 parts of2-[(p-chlorophenyl)thio]ethylamine, 24 parts of bromoacetic acid, 9parts of sodium methoxide, and 625 parts of tert.-butyl alcohol isheated at the boiling point under reflux for 12 hours, then chilled.Insoluble solids are filtered out, washed with ether, and dried in air.The product thus isolated is N-[2-(p-chlorophenylthio)ethyl1glycine.

B. N-[Z-(p-Chlorophenylthio)ethyl]-N- nitrosoglycine. A mixture of 40parts of N-{Z-(pchlorophenylthio)ethyllglycine, l2 parts of sodiumnitrite, 250 parts of water, and 214 parts of dichloromethane is stirredat 0 for 2 hours, whereupon 50 parts of concentrated hydrochloric acidis introduced. A further 12 parts of sodium nitrite is then addedportionwise with stirring during 4 hours at 0, after which stirring iscontinued at 05 1 for 15 hours. The resultant mixture is filtered, thefiltrate is extracted with dichloromethane, and the extract is washedwith water and then extracted in turn with saturated aqueous sodiumbicarbonate. The bicarbonate extract is acidified with concentratedhydrochloric acid, and the resultant mixture is extracted withdichloromethane. Evaporation of solvent affordsN-[2-(p-chlorophenylthio)ethyl]-N- nitrosoglycine as the residue.

C. 3-[2-(p-Chlorophenylthio)ethyl)sydnone. A mixture of 12 parts ofN-[2-(p-chlorophenylthio)ethylLN- nitrosoglycine and 216 parts of aceticanhydride is maintained at room temperatures under nitrogen for 4 days,then poured into 500 parts of water. The resultant mixture is stirredfor 2 hours at room temperatures, then extracted with dichloromethane.The dichloromethane extract is consecutively washed with water,saturated aqueous sodium bicarbonate, and water, then stripped ofsolvent by vacuum distillation. The residue is3-[2-(p-chlorophenylthio)ethyllsydnone which, recrystallized from amixture of acetone and ether, melts at 66-68.

EXAMPLE 3 3-[2-(Phenylsulfinyl)ethyl]sydnone. A mixture of 3 parts of3-[2-(phenylthio)ethyllsydnone and 9 parts of sodium periodate inapproximately parts of 1:2 (by volume) methyl alcoholzwater is stirredat 48 for 24 hours. Insoluble solids are filtered out and washed withchloroform. Filtrate and wash liquor are combined, and the resultantsolution is washed with water and then stripped of solvent by vacuumdistillation, leaving 3-[ 2- (phenylsulfinyl)ethyl]sydnone which,recrystallized from a mixture of acetone and ether, melts atapproximately 1 l8l 19. The product has the formula EXAMPLE 43-[2-(Phcnylsulfonyl)ethyllsydnone. A mixture of 4 parts of3-[2-(phenylthio)ethyl]sydnone and 20 parts of sodium periodate inapproximately 200 parts of 50% aqueous methyl alcohol is stirred at roomtemperatures 0 1: N 0 GD 1 It NCH CH S EXAMPLE A.N-l2-(Phenylthio)ethyllalanine. A mixture of 35 parts of3-(phenylthio)ethylamine, 35 parts of 2- bromopropionic acid, [6 partsof potassium carbonate, and 360 parts of tetrahydrofuran is heated atthe boiling point under reflux for hours. The reaction mixture is thencooled to room temperature, whereupon insoluble solids are filtered out,washed with hexane, and dried in air. The product thus isolated is N-[2-(phenylthio)ethyllalanine.

B. N-Nitroso-N-[2-(phenylthio)ethyl]alanine. To a stirred suspension of40 parts of N-[2-(phenylthio)ethyl]alanine in 525 parts of acetic acidat room temperature is slowly added a solution of l8 parts of sodiumnitrite in parts of water. Stirring is continued for 2 hours, whereuponthe reaction mixture is poured into water. The resultant mixture isextracted with dichloromethane. The dichloromethane extract is washedwith water and extracted, in turn, with saturated aqueous sodiumbicarbonate. The bicarbonate extract is acidified with concentratedhydrochloric acid. The mixture thus obtained is extracted withdichoromethane. From this extract, on evaporation of solvent,N-nitroso-N-[Z- (phenylthio)ethyl]alanine is obtained as the residue.

C. 4-Methyl-3-l2-(phenylthio)ethyllsydnone. A mixture of 17 parts ofN-nitroso-N-[2-(phenylthio)ethyl- )alanine and 65 parts of aceticanhydride is heated at 55-60 for 3 hours, then poured into 200 parts ofwater. The resultant mixture is stirred for l hour, then extracted withdichloromethane. The dichloromethane extract is consecutively washedwith water, saturated aqueous sodium bicarbonate, and water, thenstripped of solvent by vacuum distillation. The residue is 4-methyl-3-[Z-(phenylthio)ethyllsydnone which, recrystallized from amixture of acetone and ether, melts at 69-7l. The product has theformula O 1:: E (D N C NGH CH S EXAMPLE 6 Substitution of an equivalentquantity of N-nitroso- N-[2(phenylthio) ethyll-2-propylglycine for theN- nitroso-N-[2-(phenylthio)ethyllglycine called for in Example 10, andincreasing the amount of acetic anhydride to approximately 215 parts,affords, by the procedure there detailed. 3-l2-(phenylthio)ethyl]-4-propylsydnone melting at 49.55 1 .5

EXAMPLE 7 A. N-[2-(p-Tolylthio)ethyllalanine. Substitution of 50 partsof 2(p-tolylthio)ethylamine and 38 parts of 2-bromopropionic acid forthe 2-{(p-chlorophenyl)thiolethylamine and bromoacetic acid called forin Example 2A, and increasing the amounts of sodium methoxide andtert-butyl alcohol to 27 and 900 parts, respectively, affords, by theprocedure there detailed, N-[2- (p-tolylthio)ethyllalanine.

B. N-Nitroso-N-[2-(p-tolylthio)ethyl]alanine. To a mixture of 52 partsof N-[Z-(p-tolylthio)ethyllalanine. 24 parts of concentratedhydrochloric acid, 350 parts of water, and 535 parts of dichloromethaneis slowly added, with stirring at 0, a solution of 14 parts of sodiumnitrite in 50 parts of water. Stirring at 0 is continued for 4 hoursafter the addition is complete, whereupon the aqueous phase is separatedand extracted with dichloromethane. The extract is combined with theorganic phase of the reaction mixture, and the resultant solution iswashed with water and then extracted with saturated aqueous sodiumbicarbonate. The bicarbonate extract is acidified, and the resultantmixture is extracted with dichloromethane. Evaporation of solventaffords N-nitroso-N-[2(p-tolylthio)ethyl]alanine as the residue. C.4Methyl-3[Z-(p-tolylthio)ethyllsydnone. A mixture of 20 parts ofN-nitroso-N-[2-(p-tolylthio )ethyllalanine and 215 parts of aceticanhydride is maintained at room temperatures under nitrogen for 4 days,then poured into 500 parts of water. The resultant mixture is stirredfor 2 hours at room temperatures, then extracted with dichloromethane.The dichloromethane extract is consecutively washed with water,saturated aqueous sodium bicarbonate, and water, then stripped ofsolvent by vacuum distillation. The residue is 4-methyl-3-[2-(p-tolylthio)ethyl]sydnone.

EXAMPLE 8 A. N-l2-(p-tert.-Butylphenylthio)ethyl]alanine. Substitutionof 34 parts of 2-[(p-tert.-butylphenyl)thiolethylamine and 25 parts of2-bromopropionic acid for the 2-[(p-chlorophenyl)thiolethylamine andbromoacetic acid, respectively, called for in Example 2A, and decreasingthe amount of tert.-butyl alcohol to 545 parts, affords, by theprocedure detailed in the aforesaid example,N-[2-(p-tert.-butylphenylthio)ethyllalanine which, recrystallized fromwater, melts at l97-200.

B. N-[ 2-( p-tert.-Butylphenylthio )ethyl]N- nitrosoalanine. A mixtureof 40 parts of N-[2-(p-tert.- butylphenylthio)ethyllalanine, 10 parts ofsodium nitrite, 300 parts of water, and U5 parts of dichloro methane isstirred at 0 for 2 hours, whereupon 35 parts of concentratedhydrochloric acid is introduced. A further 10 parts of sodium nitrite isthen added portionwise with stirring during 4 hours at 0, after whichstirring is continued at 0-5 for 15 hours. The resultant mixture isfiltered, the filtrate is extracted with dichloromethane, and theextract is washed with water and then extracted in turn with saturatedaqueous sodium bicarbonate. The bicarbonate extract is acidified withconcentrated hydrochloric acid. and the resultant mixture is extractedwith dichloromethane. Evaporation fo solvent affordsN-[2-(p-tert.-butylphenylthio)ethyll-N- nitrosoalanine as the residue.

C. 3-l2-(p-terL-Butylphenylthio)ethyl]-4- methylsydnone. A mixture of 2lparts of N-{ 2-(p-tert.-

butylphenylthio)ethyl]-N-nitrosoalanine and 2l5 parts of aceticanhydride is maintained at room temperatures under nitrogen for 4 clays,then poured into 500 parts of water. The resultant mixture is stirredfor 2 hours at room temperatures, then extracted with dichloromethane.The dichloromethane extract is consecutively washed with water,saturated aqueous sodium bicarbonate, and water, then stripped ofsolvent by vacuum distillation. The residue is chromatographed onneutral alumina, using benzene and mixtures thereof with increasingamounts of ethyl acetate as developing sol vents. From an eluatecomprising 5% ethyl acetate in benzene, on evaporation of solvent andrecrystallization of the residue from ether, 3-l2-(p-tert.-butylphenylthio)ethyll-4-methylsydnone melting at approxi. ately 606l isobtained.

EXAMPLE 9 A. 2-tert.-Butyl-N-[2(p-tert.-butylphenylthio)ethyl]glycine.Substitution of 49 parts of 2-(p-tert. butylphenylthio)ethylaminehydrochloride and 39 parts of 2-bromo-2-tert.-butylacetic acid for the2-[(pchlorophenyl)thio]ethylamine and bromoacetic acid called for inExample 2A, and increasing the amounts of sodium methoxide andtert.-butyl alcohol to 22 and 780 parts, respectively, affords, by theprocedure detailed in the aforesaid example,2-tert.-butyl-N-[2-(ptert.-butylphenylthio)ethyllglycine which,recrystallized from methyl alcohol, melts at approximately l97-l98.

B. 2 tert.-Butyl-N-[2-(p-tert.-butylphenylthio)ethyl]- N-nitrosoglycine.Substitution of 58 parts of 2-tert.-butyl-N-[2-(p-tert.-butylphenylthio)ethyllglycine for theN-[2-(p-tolylthio)ethyl]alanine called for in Example 7B, and increasingthe amount of hydrochloric acid to 35 parts, affords, by the proceduredetailed in the aforesaid example, 2-tert -butyl-N-[2-(p-tert.-butylphenylthio)ethyl]-N-nitrosoglycine.

C. 4 tert.-Butyl-3-[2-(p-tert.-butylphenylthio)ethyllsydnone. A mixtureof 2-tert.-butyl-N-[2-(p-tert.- butylphenylthio)ethyl]-N-nitrosoglycineand 325 parts of acetic anhydride is maintained at room temperaturesunder nitrogen for 4 days, then poured into 500 parts of water. Theresultant mixture is stirred for 2 hours at room temperatures, thenextracted with dichloromethane. The extract is consecutively washed withwater, saturated aqueous sodium bicarbonate, and water, then stripped ofsolvent by vacuum distillation. The residue is 4-tert.-butyl-3-[2-(p-tert.-butylphenylthio)ethyl]sydnone which, recrystallized from amixture of ethyl alcohol and ether, melts at approximately 86-87.

EXAMPLE l0 A. N-[4-(m-tert.-Butylphenylthio)butyllalanine. Substitutionof 39 parts of 4-[(m-tert.-butylphenyl)thio]butylamine and 25 parts of2-bromopropionic acid for the 2-(phenylthio)ethylamino and 2-bromoacticacid called for in Example 2A, and decreasing the amount of tert.-butylalcohol to 545 parts, affords, by the procedure detailed in theaforesaid example, N-[4- (m-tert.-butylphenylthio)butyllalanine.

B. N-[4-(m-tert.-Butylphenylthio)hutyll-N- nitrosoalanine. Substitutionof 44 parts of N-[4-(mtert-butylphcnylthio)butyllalanine for theN-[2(ptert.-butylphenylthio)cthyllalanine called for in Example 8Baffords, by the procedure there detailed, N-[4-(m-terL-butylphenylthio)butyl]-N-nitrosoalanine.

C. 3-[4-(m-terL-Butylphenylthio)butyl] 4- methylsydnone. Substitution of17 parts of N-[4-(mtert.-butylphenylthio)butyl]-N-nitrosoalanine for theN-nitroso-N-[2-(p-tolylthio)ethyllalanine called for in Example 7Caffords, by the procedure there detailed,3-[4-(m-tert.-butylphenylthio)butyl]-4- methylsydnone. The product hasthe formula NCH CH CH CH S EXAMPLE ll A.N-[2-(o-tert.-Butylphenylthio)ethyl]alanine. Substitution of 34 parts of2-[(o-tert.-butylphenyl)thiolethylamine and 25 parts of 2-bromopropionicacid for the 2-[(p-chlorophenyl)thio]ethylamine and bromoa cetic acid,respectively, called for in Example 2A, and decreasing the amount oftert.-buty1 alcohol to 545 parts, affords, by the procedure detailed inthe aforesaid example, N-[2-(o-tert.-butylphenylthio)ethyllalanine.

B. N[2-(o tert.-Butylphenylthio)ethyll-N- nitrosoalanine. Substitutionof 40 parts of N-[2-(otert.-butylphenylthio)ethyllalanine for theN-[2-(ptert.butylphenylthio)ethyllalanine called for in Exam ple 8Baffords, by the procedure there detailed, N-[Z-(o-tert.-butylphenylthio)ethyll-n-nitrosoalanine.

3. 3[2-(o-tert-Butylphenylthio)ethyl]-4- methylsydnone. Substitution of20 parts of N[2-(otert.-butylphenylthio)ethyll-N-nitrosoalanine for theN-nitroso-N[2-(ptolylthio)ethyl]alanine called for in Example 7Caffords, by the procedure there detailed,3-[2-(o-tert.-butylphenylthio)ethyll-4-methylsydnone.

EXAMPLE l2 A. N-{Z-(p-Fluorophenylthio)ethyl]alanine. Substitution of 29parts of 2-[(p-fluorophenyl)thiojethylamine and 26 parts ofZ-bromopropionic acid for the 2- [(p-chlorophenyl)thio]ethylamine andbromoacetic acid, respectively, called for in Example 2A affords, by theprocedure there detailed, N[2-(pfluorophenylthio)ethyl]alanine.

B. N-[2-(p-Fluorophenylthio)ethyll-N- nitrosoalanine. Substitution of 35parts of N-[2-(pfluorophenylthio)ethyl]alanine for the N-[2-(pterL-butylphenylthio)ethyllalanine called for in Example 88 affords, by theprocedure there detailed,N-[2(pfluorophenylthio)ethyl]-N-nitrosoalanine.

C. 3-[2-(p-Fluorophenylthio)ethyll-4- methylsydnone. Substitution of 15parts of N-{IZ-(pfluorophenylthio)ethyl-N-nitrosoalanine for the N-nitroso-N-[2(p-tolylthio)ethyl]alanine called for in Example 7C affords,by the procedure there detailed,3-[Z-(p-fluorophenylthio)ethyl]4-methylsydnone.

EXAMPLE 13 A. N-[2-(o-Fluorophenylthio)ethyllalanine. Substitution of 29parts of 2-[ethylamine and 26 parts of 2- bromopropionic acid for the2l(p-chlorophenyl)thio]ethylamine and bromoacetic acid, respectively,called for in Example 2A, and decreasing the amount of tert.-butylalcohol to 390 parts, affords, by the procedure detailed in theaforesaid example, N-[2-(ofluorophenylthio)ethyl]alanine.

B. N-[2-(o-Fluorophenylthio)ethyll-N- nitrosoalanine. Substitution of 35parts of N-[2-(ofluorophenylthio)ethyllalanine for the N-[2-(p-tert.-butylphenylthio)ethyllalanine called for in Example 88 affords, by theprocedure there detailed, N-[Z-(ofluorophenylthio)ethyllN-nitrosoalanine.

C. 3-lZ-(O-Fluorophenylthio)ethyl1-4- methylsydnone. Substitution of 16parts of N-{Z-(ofluorophenylthio)ethyl]-N-nitrosoalanine for the N-nitroso-N-l2-(p-tolylthio)ethyl]alanine called for in Example 7Caffords, by the procedure there detailed,3-[2-(o-fluorophenylthio)ethyl1-4-methylsydnone.

EXAMPLE 14 A. N-[2-(p-Chlorophenylthio)ethyl]alanine. Substitution of 32parts of 2-Hp chlorophenyl)thio]ethylamine and 26 parts of2-bromopropionic acid for the 2- [(p-chlorophenyl)thio]ethylamine andbromoacetic acid, respectively, called for in Example 2A, and decreasing the amount of tert-butyl alcohol to 390 parts, affords, by theprocedure detailed in the aforesaid example,N-[2-(pchlorophenylthiolethyllalanine which, recrystallized from water,melts at approximately 2l9-220.

B. N-[2-(p-Chlorophenylthio)ethyl]-N nitrosoalanine. A mixture of 42parts of N [2 (p chlorophenylthio)ethyl]alanine, 11 parts of sodiumnitrite, 250 parts of water, and 135 parts of dichloromethane is stirredat for 2 hours, whereupon approx imately 50 parts of hydrochloric acidis introduced. A further I l parts of sodium nitrite is then addedportionwise with stirring during 4 hours at 0, after which stirring iscontinued at O-5 for 15 hours. The resultant mixture is filtered, thefiltrate is extracted with dichloromethane, and the extract is washedwith water and then extracted in turn with saturated aqueous sodiumbicarbonate. The bicarbonate extract is acidified with concentratedhydrochloric acid, and the resultant mix ture is extracted withdichloromethane. Evaporation of solvent affordsN-l2-(p-chlorophenylthio)ethyl]N- .ntrosoalanine as the residue.

C. 3-[ 2-(p-Chlorophenylthio)ethyl1-4- methylsydnone, Substitution of 23parts of N-[Z-(pchlorophenylthio)ethyl]-N-nitrosoalanine for the N-{Z-(p-chlorophenylthio )ethyll-N-nitrosoglycine called for in Example 2Caffords, by the procedure there detailed,3-[2-(pchlorophenylthio)ethyl]'4- methylsydnone melting at approximately7778.

EXAMPLE 15 A. Nl2-(o-Bromophenylthio)ethyl]alanine. Substi tution of 42parts of 2-[(o-bromophenyl)thio]ethylamine and 26 parts of2'bromopropionic acid for the 2- [(p-chlorophenyl)thio]ethylamine andbromoacetic acid, respectively, called for in Example 2A, and decreasingthe amount of tert-butyl alcohol to 390 parts, affords, by the proceduredetailed in the aforesaid example,N-I2-(o-bromophenylthio)ethyl1alanine.

B, N-[Z-(o-Bromophenylthio)ethyll N- nitrosoalanine. Substitution of 49parts of N-l2(o bromophenyl)cthyllalanine for the N-[2'(pchlorophenylthiolethyllalanine called for in Example 148 affords, by theprocedure there detailed,N-[Z-(obromophenylthio)ethyl]-N-nitrosoalanine.

C. 3-l2-(o-Bromophenylthio)ethyl]-4- methylsydnone. Substitution of 20parts of N-[Z-(obromophenylthio)ethyll-N-nitrosoalanine for the N-nitroso-N-[2(p-tolylthio)ethyllalanine called for in Example 7C affords,by the procedure there detailed,3-[2-(o-bromophenylthio)ethyl]-4-methylsydnone.

EXAMPLE 16 A. N-[2-(p-lodophenylthio)ethyllalanine. Substitution of 48parts of 2-l(p-iodophenyl)thiolethylamine and 26 parts of2-bromopropionic acid for the 2-[(pchlorophenyl)thio]ethylamine andbromoacetic acid, respectively, called for in Example 2A, and decreasingthe amount of tert.-butyl alcohol to 390 parts, affords, by theprocedure detailed in the aforesaid example, N-l2-(p-iodophenylthiolethyllalanine.

B. N-[2-(p-Iodophenylthio)ethyl]-N-nitrosoalanine. Substitution of 56parts of N{2-(p-iodophenylthio)ethyl]alanine for theN-[Z-(p-chlorphenylthio )ethyllalanine called for in Example 14B,affords, by the proce dure there detailed, N-[2(p-iodophenylthio)ethyl]-N- nitrosoalanine.

C. 3-[2-(p-lodophenylthio)ethyl]4-methylsydnone. Substitution of 23parts of N-l2-(p-iodophenylthio)ethyll-N-nitrosoalanine for theN-nitroso-N-[2-(ptolylthio)ethyl]alanine called for in Example 7Caffords, by the procedure there detailed,3-[2-(piodophenylthio)ethyl]-4-methylsydnone.

EXAMPLE l7 A. N-[2-(2,5-Dichlorophenylthio)ethyllalanine. Substitutionof 43 parts of 2-[(2,5-dichlorophenyllthiolethylamine and 30 parts of2-bromopropionic acid for the 2-[(p-chlorophenyl)thio]ethylamine andbromoacetic acid, respectively, called for in Example 2A, and increasingthe amount of sodium methoxide to 10 parts, affords, by the procedurethere detailed, N- l2-(2,5-dichlorophenylthio)ethyl]alanine.

B. N-[242,5-dichlorophenylthio )ethyl]-N- nitrosoalanine. To a mixtureof 40 parts of N-[2-(2,5- dichlorophenylthio)ethyllalanine, 30 parts ofconcentrated hydrochloric acid, 300 parts of water, and 270 parts ofdichloromethane is slowly added, with stirring at 0, a solution of 14parts of sodium nitrite in 50 parts of water. Stirring at 0 is continuedfor 4 hours after the addition is complete, whereupon the aqueous phaseis separated and extracted with dichloromethane, The extract is combinedwith the organic phase of the reaction mixture, and the resultantsolution is washed with water and then extracted with saturated aqueoussodium bicarbonate. The bicarbonate extract is acidified, and theresultant mixture is extracted with dichloromethane. Evaporation ofsolvent affords N-[ 2-( 2,5 dichlorophenylthio)ethyl l N'nitrosoalanincas the residue.

C, 3-[ 2-(2,5-Dichlorophenylthio)ethyllA- methylsydnone. Substitution of24 parts of N-l2-(2,5- dichlorophenylthio)ethyll-N-nitrosoalanine forthe N- [2(p-chlorophenylthio)ethyl]Nnitrosoglycine called for in Example2C affords, by the procedure there detailed,3-[2-(2,S-dichlorophenylthio)ethyll-4 mcthylsydnone melting atapproximately 74-75.

EXAMPLE l8 A, N|2-(3,4-Dichlorophenylthio)cthyl]alanine. Substitution of43 parts of 2-[( 3,4-dichlorophenyl)thiol-ethylamine and 30 parts ofZ-bromopropiomc acid for the 2-[(p-chlorophenyl)thiolethylamine andbromoacetic acid, respectively, called for in Example 2A, and reducingthe amount of sodium methoxide to parts, affords, by the proceduredetailed in the aforesaid example,N-[2-(3,4-dichlorophenylthio)ethyllalanine.

B. N-[2-( 3 ,4-Dichlorophenylthio )ethyl l-N- nitrosoalanine.Substitution of 36 parts of N-[2-(3,4- dichlorophenylthio)ethyllalaninefor the N-[2-(2,5- dichlorophenylthio)ethyllalanine called for inExample 178 affords, by the procedure there detailed, N-[Z-(3,4-dichlorophenylthio)ethyl]-N-nitrosoalanine.

C. 3-[2-(3,4-Dichlorophenylthio)ethyll-4- methylsydnone. A mixture of 13parts of N-[2-(3,4- dichlorophenylthio)ethyll-N-nitrosoalanine and 215parts of acetic anhydride is maintained at room temperatures undernitrogen for 4 days, then poured into 500 parts of water. The resultantmixture is stirred for 2 hours at room temperatures, then extracted withdichloromethane. The dichloromethane extract is consecutively washedwith water, saturated aqueous sodium bicarbonate, and water, thenstripped of solvent by vacuum disillation. The residue is 3-[2-(3,4-dichlorophenylthio)ethyl]-4-methylsydnone which, recrystallized fromethyl acetate, melts at approximately 85.

EXAMPLE 19 A. N-[Z-(p-Methoxyphenylthio)ethyl1alanine. Substitution of39 parts of Z-l(p-methoxyphenyl)thio]- ethylamine and 33 parts of2-bromopropionic acid for the 2-[(p-chlorophenyl)thio]ethylamine andbromoacetic acid called for in Example 2A, and increasing the amounts ofsodium methoxide and tert.-butyl alcohol to l2 and 700 parts,respectively, affords, by the procedure detailed in the aforesaidexample, N-[2-(pmethoxyphenylthio)ethyll-alanine.

B. N-[2(p-Methoxyphenylthio)ethyl]-N- nitrosoalanine. A mixture of 40parts of N-[2-(pmethoxyphenylthio)ethyl1alanine, 14 parts of sodiumnitrite, 300 parts of water, and 270 parts of dichloromethane is stirredat 0 for 2 hours, whereupon 60 parts of concentrated hydro-chloric acidis introduced. A further 14 parts of sodium nitrite is then addedportionwise with stirring during 4 hours at 0, after which stir ring iscontinued at for 15 hours. The resultant mixture is filtered, thefiltrate is extracted with dichloromethane, and the extract is washedwith water and then extracted in turn with aqueous sodium bicarbonate.The bicarbonate extract is acidified with concentrated hydrochloricacid, and the resultant mixture is extracted with dichloromethane.Evaporation of solvent affords N-lZ-(p-methoxyphenylthio)-ethyl]-N-nitrosoalanine as the residue.

C. 3-[2-(p-Methoxyphenylthio)ethyll-4- methylsydnone. A mixture of l4parts of N-[Z-(pmethoxyphenylthio)ethyll-N-nitrosoalanine and 215 partsof acetic anhydride is maintained at room temperatures under nitrogenfor 4 days, then poured into 500 parts of water. The resultant mixtureis stirred for 2 hours at room temperatures, then extracted withdichloromethane. The dichlormethane extract is consecutively washed withwater, saturated aqueous sodium bicarbonate. and water, then stripped ofsolvent by vacuum distillation. The residue is 3-[2(pmethoxyphenylthio)ethyl l-4-methylsydnone which, re-

crystallized from a mixture of acetone and ether. melts at approximately-6 l EXAMPLE 2() A. N-[2-(o-Ethoxyphenylthio)ethyllalanine. Substitutionof 42 parts of 2-[(o-ethoxyphenyl)thio]- ethylamine and 33 parts of2-bromopropionic acid for the 2[(p-chlorophenyl)thiolethylamine andbromoacetic acid called for in Example 2A, and increasing the amounts ofsodium methoxide and tert.-butyl alcohol to 10 and 700 parts,respectively, affords, by the procedure detailed in the aforesaidexample, N-[2-(oethoxyphenylthio)ethyllalanine.

B. N-[2(o-Ethoxyphenylthio)ethyl]-N- nitrosoalanine. Substitution of 62parts of N-[Z-(oethoxyphenylthio)ethyllalanine for the N-[2-(2,5-dichlorophenylthio)ethyl]alanine called for in Example 17B, anddecreasing the amounts of sodium nitrite and hydrochloric acid to 12 to15 parts, respectively, affords, by the procedure detailed in theaforesaid example, N-[2-(o-ethoxyphenylthio)-ethyl]-N- nitrosoalanine.

C 3-[2-(o-Ethoxyphenylthio)ethyl]-4- EXAMPLE 2] A.N-l2-(p-Nitrophenylthio)ethyllalanine. A mixture of 50 parts of2-[(p-nitrophenyl)thio]ethylamine hydrochloride, 33 parts ofZ-bromopropionic acid, 23 parts of sodium methoxide, and 545 parts oftert.-butyl alcohol, is heated at the boiling point under reflux for 12hours, then cooled to room temperature. Insoluble solids are filteredout, washed with ether and dried in air. The product thus isolated isN-[2 (p nitrophenylthio)-ethyl]alanine.

B. N-[Z-(p-Nitrophenylthio)ethyl]-N-nitrosoalanine. To a mixture of 62parts of N-[2-(p-nitrophenylthio)e thyl]alanine, approximately 20 partsof concentrated hydrochloric acid, 250 parts of water, and 270 parts ofdichloromethane is slowly added, with stirring at 0, a solution of 12parts of sodium nitrite in 50 parts of water. Stirring at 0 is continuedfor 4 hours after the addition is complete, whereupon the aqueous phaseis separated and extracted with dichloromethane. The extract is combinedwith the organic phase of the reaction mixture, and the resultantsolution is washed with water and then extracted with saturated aqueoussodium bicarbonate. The bicarbonate extract is acidified, and theresultant mixture is extracted with dichloromethane, Evaporation ofsolvent affords N-[ 2( p nitrophenylthio)ethyl]-N nitrosoalanine as theresidue.

C. 3-[Z-(p-Nitrophenylthio)ethyl]-4-mcthylsydnone. Substitution of 3|parts of N-[2-(p-nitrophenylthio)ethyll-N-nitrosoalanine for the N-[ 2(3,4- dichlorophenylthio)ethylLN-nitrosoalanine called for in Examplel8C, and increasing the amount of acetic anhydride to 325 parts,affords, by the procedure de tailed in the aforesaid example,3-{2-(pnitrophenylthio)ethyll-4-methylsydnone melting at 205207.

EXAMPLE 22 4-Methyl-3-[ Z-(phenylsulfmyl )cthyl ]sydnonc. A

mixture of 10 parts of 4-methyl-3-[2-(phenylthio)ethyl]-sydnone and 22parts of sodium periodate in approximately 300 parts of 1:6 (by volume)methyl alcohol: water is stirred at 48 for 24 hours. lnsoluble solidsare filtered out and washed with chloroform. Filtrate and wash liquorare combined, and the resultant solution is washed with water and thenstripped of solvent by vacuum distillation, leaving 4-methyl-3-[2-(phenylsulfinyl)ethyll-sydnone as the residue.

EXAMPLE 23 A. N-[3-(Phenylthio)propyllalanine, Substitution of 40 partsof 3-(phenylthio)propylamine and 37 parts of Z-bromopropionic acid forthe 2-[(phenylthio)propylamine and 37 parts of l-bromopropionic acid forthe 2- [(p-chlorophenyl)thioi-ethylamine and bromoacetic acid called forin Example 2A, and increasing the amounts of sodium methoxide andtert.-butyl alcohol to l3 and 780 parts, respectively, affords, by theprocedure detailed in the aforesaid example, N-[S-(phenylthio)propyllalanine which, recrystallized from water, melts atapproximately 265".

B. N-Nitroso-N-[3-(phenyisulfinyl)propyl]alanine. Substitution of 85parts of N-[3 (phenylthio)propyllalanine for the bariumN-[2-(phenylthio)ethyl]glycinate called for in Example 1C, andincreasing the amounts of sodium nitrite, hydrochloric acid, and waterto 34, 60, and 300 parts, respectively, affords, by the proceduredetailed in the aforesaid example, N- nitroso-N-i 3phenylsulfinyl)-propyl Ialanine.

C. 4-Methyl-3-[3- phenylsulfinyl)propyllsydnone. A mixture of 34 partsof N-nitroso-N-[3-(phenylsulfinyl)- propy11alanine and 215 parts ofacetic anhydride is maintained at room temperature under nitrogen for 4days, then poured into 500 parts of water. The resultant mixture isstirred for 2 hours at room temperatures, then extracted withdichloromethane. The dichloromethane extract is consecutively washedwith water, saturated aqueous sodium bicarbonate, and water, thenstripped of solvent by vacuum distillation. The residue is4-methyl-3-[3-(phenylsulfinyl)propylisydnone which, recrystallized fromacetone, melts at approximately 128".

EXAMPLE 24 A. N-{4-(Phenylthio)butyHalanine. Substitution of 43 parts of4-(phenylthio)butylamine and 37 parts of Z-bromopropionic acid for the2-[(p-chlorophenyl)thio]-ethylamine and bromoacetic acid called for inExample 2A, and increasing the amounts of sodium methoxide andtert.-butyl alcohol to 13 and 780 parts, re spectively, affords, by theprocedure detailed in the aforesaid example,N-[4-(phenylthio)butyl1alanine.

B. N-NitrosoN-[4-(phenylsulfinyl)butyl]alanine. Substitution of 90 partsof N-I4-(phenylthio)butyl]alanine for the bariumN-{2-(phenylthio)ethyllglycinate called for in Example lC, andincreasing the amounts of sodium nitrite, hydrochloric acid, anddichloromethane to 34, 70, and 200 parts, respectively. affords, by theprocedure detailed in the aforesaid example, Nnitroso-N-[4-(phenylsulfinyl)butyllalanine.

C. 4-Methyl3-[4-(phenylsulfinyl)butyllsydnone. Substitution of 21 partsof N-nitroso-N-[4-(phenylsulfinyh-butyllalanme for theNnitroso-N-l2-(p-tolylthio)ethyl]-alanine called for in Example 7Caffords, by the procedure there detailed, 4-methyl-3[4-(phenylsulfinyl)butyllsydnone.

EXAMPLE 25 A, N] 2-(Benzylthio)ethylialanine. Substitution of 40 partsof 2-(benzylthio)ethylamine for the 2-[(p nitrophenyl)thio]ethylaminehydrochloride called for in Example 21A, and decreasing the amounts of2- bromopropionic acid and sodium methoxide to 31 and 11 parts,respectively, affords, by the procedure detailed in the aforesaidexample, N-[2-(benzylthio)ethyl]alanine which, recrystallized fromwater, melts at approximately 2 l 9220.

B. N-[2-(Benzylsulfinyl)ethyl]-N-nitrosoalanine. A mixture of 86 partsof N-[2-(benzylthio)ethyllalanine, 25 parts of sodium nitrite, 600 partsof water, and 270 parts of dichloromethane is stirred at 0 for 2 hours,whereupon 95 parts of concentrated hydrochloric acid is introduced. Afurther 25 parts of sodium nitrite is then added portionwise withstirring during 4 hours at 0, after which stirring is continued at O5for [5 hours. The resultant mixture is filtered, the filtrate isextracted with dichloromethane, and the extract is washed with water andthen extracted in turn with saturated aqueous sodium bicarbonate. Thebicarbonate extract is acidified with concentrated hydrochloric acid,and the resultant mixture is extracted with dichloromethane. Evaporationof solvent affords N-[2 (Benzylsulfinyl)ethyll-N-nitrosoalanine as theresidue.

C. 3-[2 (Benzylsulfinyl)ethyl]-4 methylsydnone. A mixture of ll parts ofN-[2-(benzylsulfinyUethylLN- nitros oalanine and parts of aceticanhydride is maintained at room temperature under nitrogen for 4 days,then poured into 500 parts of water. The resultant mixture is stirredfor 2 hours at room temperatures, then extracted with dichloromethane.The dichloromethane extract is consecutively washed with water,saturated aqueous sodium bicarbonate, and water, then stripped ofsolvent by vacuum distillation. The residue is3-[2-(benzylsulfinyl)-ethyl]-4-methylsydnone which, recrystallized fromacetone, melts at 82-84. The product has the formula 0 O 0 C 1 i C NCHCH SCH EXAMPLE 26 3-[2-(o-tert.Butylphenylsulfinyhethyl1-4-methylsydnone. Substitution of i0 parts of3-[2-(otert.-butylphenylthio)ethyll-4-methylsydnone for the4-methyl-3-[2-(phenylthio)ethyl]sydnone called for in Example 22affords, by the procedure there detailed,3-[2(o-tert.butylphenylsulfinyl)ethyl}4- methylsydnone.

EXAMPLE 27 A. N-Nitroso-N-[2(p tolylsu1finyl)ethyl]alanine. Substitutionof 19 parts of N-[2-(p-tolylthio)ethyl]alanine for theN-[Z-(phenylthio)ethyllalanine called for in Example 513, and decreasingthe amounts of sodium nitrite and acetic acid to 7 and 210 parts,respectively, affords, by the procedure detailed in the aforesaidexample, N-nitroso-N-{2-(p-tolylsulfinyl)ethyllalanine.

B. 4-Methyl-3-[ 2-( p-tolylsulfinyl )ethyl lsydnone. Substitution of 19parts of N-nitroso-N [2-(p-tolylsulfinyl)-ethyl]alanine for theN-nitroso-N-l 3-(phenylsulfinyl)propyl]-alanine called for in Example23C, and decreasing the amount of acetic anhydride to I60 parts,affords, by the procedure detailed in the aforesaid example,4-methyl-3-[2 (p-tolylsulfinyl)ethyllsydnone, melting at approximately103.

EXAMPLE 28 methylsydnone. Substitution of 20 parts of3-[2-(ptert.-butylphenylthio)ethyl]-4-methylsydnone and approximately650 parts of 1:6 (by volume) methyl alcohol:water for the3-[2-(phenylthio)ethyllsyclnone and 1:2 methyl alcoholzwater called forin Example 3, respectively, affords, by the procedure there detailed,3-12-(, -terL-butylphenylsulfinyl)ethyl]-4- methylsydnone melting atlll03.

EXAMPLE 29 3-[2 (o-Fluorophenylsulfinyl)ethyl]-4- methylsydnone.Substitution of 3 parts of 3-[2-(0-fluorophenylthio)ethyl]-4-methylsydnone and approximately 50 parts of1:2 (by volume) methyl alcoholzwater for the4-methyl-3-lZ-(phenylthio)ethyllsydnone and 1:6 methyl alcohol:water,respectively, called for in Example 22, and decreasing the amount ofsodium per iodate to 8 parts, affords, by the procedure detailed in theaforesaid example, 3-[ 2-(0-fluorophenylsulfinyl)ethyl]-4-methylsydnone.

EXAMPLE 30 EXAMPLE 31 3-[2-(p-lodophenylsulfinyl)ethyl]-4-methylsydnone.Substitution of 4 parts of 3-{2-(piodophenylthio)ethyll'4-methylsydnoneand approximately 100 parts of 1:4 (by volume) methyl alcohol:- waterfor the 4-methyl-3-]2-(phenylthio)ethyl]sydnone and 1:6 methylalcohol:water respectively, called for in Example 22, and decreasing theamount of sodium periodate to 8 parts, affords, by the proceduredetailed in the aforesaid example, 3-(2-(piodophenylsulfinyl)ethyl]-4-methylsydnone.

EXAM PLE 32 4Methyl-3[(p-tolylsulfonyl)ethyHsydnone. A mixture of partsof 4-methyl-3-[2-(p-tolylthio)ethyl]- sydnone and 2l parts of sodiumperiodate in approximately 160 parts of 1:5 (by volume) methyl alcohol:-water is stirred at room temperatures for 4 days. lnsolu ble solids arefiltered out and washed with chloroform. Filtrate and wash liquor arecombined; and the resultant solution is washed with water and thenstripped of solvent by vacuum distillation, leaving4-methyl-3-l(ptolylsulfonyl)-ethyl]sydnone as the residue,

EXAMPLE 33 3-[2-(p-tert.-Butylphenylsulfonyl)ethyl]-4- methylsydnone. Amixture of 20 parts of 3-[ 2-(p-tert.-butylphenylthio)ethyll-4-methylsydnone and 84 parts of sodium nitrite inapproximately 600 parts of 1:5 (by volume) methyl alcoholzwater isstirred at room temperatures for 4 days. Insoluble solids are filteredout and washed with chloroform. Filtrate and wash liquor are combined;and the resultant solution is washed with water and then stripped ofsolvent by vacuum distillation, leaving3-]2-(p-tert.-butylphenylsulfonyl)ethyl]- 4-methylsydnone as theresidue. Recrystallized from a mixture of acetone and ether, the productmelts at -l37.

EXAMPLE 34 3-[2-(o-tert.-Butylphenylsulfonyl)ethyl]-4- methylsydnone.Substitution of 5 parts of 3-[2o-tert.-butylphenylthio)ethyl]'4-methylsydnone for the 4methyl-3-[2-(p-tolylthio)ethyl]sydnone called for in Example 32 affords,by the procedure there detailed,3-[2-(o-tert.-butylphenylsulfonyl)ethyl]-4- methylsydnone.

EXAMPLE 35 A. 2-Phenyl-N-[2-(phenylthio)ethyl]glycine. A mix ture of 35parts of 2-(phenylthio)ethylamine, 49 parts of a-bromophenylacetic acid,9 parts of sodium hydroxide, and 315 parts of ethyl alcohol is heated atthe boiling point under reflux for 20 hours, then chilled. Insolublesolids are filtered out, washed with hexane, and dried in air, Theproduct thus isolated is 2 phenyl-N-[2- (phenylthio)ethyl]glycinemelting at approximately 205-206.

B. N-nitroso-2-phenyl-N-[2-(phenylthio)ethyl]glycine. Substitution of 35parts of 2-phenyl-N-[2- (phenylthio)ethyl]glycine for theN-[2-(phenylthio)ethyllalanine called for in Example 513, and decreasingthe amounts of sodium nitrite and acetic acid to 5 and 200 parts,respectively, affords, by the procedure detailed in the aforesaidexample, N-nitroso-2-phenylN- [2-(phenylthio)ethyl]glycine.

C. 4-Phenyl-3-[Z-(phenylthio)ethyllsydnone. Substitution of 12 parts ofN-nitroso-2-phenyl-N-[2- (phenylthio)ethyllglycine for theN-nitroso-N-[Z- (phenylthio)ethyl]alanine called for in Example 5C affords, by the procedure there detailed, 4-phenyL3-[2-(phenylthio)ethyl]sydnone melting at approximately 8l-82.

EXAMPLE 36 4-Bromo-3-l2-(phenylthio)ethyllsydnone. To a solution of 40parts of 3[2-(phenylthio)ethyl]sydnone and 40 parts of potassium acetatein 420 parts of acetic acid is slowly added, with stirring, a solutionof 28 parts of bromine in l05 parts of acetic acid, Stirring iscontinued until the reaction mixture becomes colorless, whereupon themixture is dumped into 500 parts of water. Insoluble solids are filteredout and recrystallized from a mixture of acetone and ether to give4-bromo-3- [2-(phenylthio)ethyllsydnone as a colorless solid melting at8688.

EXAMPLE 37 A. N-[ 2-(2-Naphthylthio)ethyl]alanine. Substitution of 50parts of 2-(2-naphthylthio)ethylamine hydrochloride and 32 parts ofZ-bromopropionic acid for the 2- [(p-chlorophenyl)thiolethylamine andbromoacetic acid called for in Example 2A, and increasing the amounts ofsodium methoxide and tert.-butyl alcohol to 23 and 1,000 parts,respectively. affords, by the procedure detailed in the aforesaidexample, N-[2(2- naphthylthio)ethyl]alanine which, recrystallized frommethyl alcohol, melts at 21 8-220.

B. N-[2-(2-Naphthylthio)ethyl]-N-nitrosoalanine. Substitution of 57parts of N-(Z-(Z-naphthylthioJethyl- ]alanine for theN-[Z-(p-tolylthio)ethyl]alanine called for in Example 78, and increasingthe amount of water to 600 parts, affords, by the procedure detailed inthe aforesaid example, N-[2-(2-naphthylthio)ethyl]-N- nitrosoalanine.

C. 4-Methyl-3-[2-(2-naphthylthio)ethyl]sydnone. Substitution of lo partsof N-[2-(2-naphthylthio)ethyll-N-nitrosoalanine for theN-[Z-(pchlorophenylthio)ethyH-Nmitrosoglycine called for in Example 2C,and increasing the amount of acetic anhydride to 325 parts, affords, bythe procedure detailed in the aforesaid example, 4-methyl-3-[2-(2-naphthylthio)ethyllsydnone melting at approximately 8l-82. The producthas the formula We H30 N-CH CH S chlorophenyl)-thio]-l-methylethylamineand 3] parts of 2-bromopropionic acid for the 2-[(p-chlorophenyl)-thio]ethylarnine and bromoacetic acid called for in Example 2A, andincreasing the amounts of sodium methoxide and terL-butyl alcohol to 22and 780 parts, respectively, affords, by the procedure detailed in theoresaid example, N-l2-(p-chlorophenylthio)-lnietnylethyllalanine.

B. N-[2-(p-Chlorophenylthio)-l-methylethyl]-N- nitrosoalanine.Substitution of 42 parts ofN-[Z-(pchlorophenylthio)-l-methylethyl]alanine for the N-[2- (ptolylthio)ethyl1alanine called for in Example 78, and decreasing theamounts of water and dichloromethane to 200 and 270 parts, respectively,affords, by the procedure detailed in the aforesaid example, N-[2-(p-chlorophenylthio)-l-methylethyl]-N- nitrosoalanine.

C. 3-[2-(p-Chlorophenylthio)-l-methylethyl]-4- methylsydnone,Stibstitution of parts ofN-[2-(pchlorophenylthio)-l-methylethyll-N-nitrosoalanine for theN-nitroso-N-[Z-(p-tolylthio)ethyl]alanine called for in example 7Caffords, by the procedure there detailed, 3-I 2-( p-chlorophenylthio-methylethyl ]-4- methylsydnone The product has the formula EXAMPLE 39A. N-[Z-(p-tert.-Butylphenylthio)ethyl]3carbome thoxyalanine. 28 Partsof maleic anhydride in 80 parts of methanol is refluxed for about 40minutes. Then the excess methanol is removed by distillation and theresidue remaining is cooled to about 0 and treated with parts oftriethylamine, added in one portion. This solution is stirred and 52parts of 2-(p-tert.-butylphenylthio)ethylamine is added. The mixturesolidifies after about l0 minutes upon warming. After filtering, thefilter cake is broken, washed with ethyl acetate and recrystallized frommethanol to give N'[2(p-tert.- butylphenylthio)ethyl]-3carbomethoxyalanine, melting at about 208.

B. N-]2-(ptert.-Butylphenylthio)ethyl]-3-carbomethoxy-N-nitrosolalanine.Substitution of 50 parts of N-[2-(p-tert.-butylphenylthio)ethyl]-3-carbomethoxyalanine, 600 parts ofwater, 400 parts of dichloromethane, 24 parts of concentratedhydrochloric acid, and 155 parts of sodium nitrite in the procedure ofExample 88, and otherwise following the procedure detailed therein,affords, N-[2-(p-tert.-butylphenylthio)ethyl]-3-carbomethoxy-N-nitrosoalanine.

C. 3[2-(p-tert.-Butylphenylthio)ethyl]-4- methoxycarbonylmethylsydnone.Substitution of 54 parts of N-[2 (p-tert.-butylphenylthio)ethyl1-3-carbomethoxy-Nnitrosoalanine and 840 parts of acetic anhydride in theprocedure of Example 7B, and otherwise following the procedure detailedtherein, affords3-]2-(p-tert.-butylphenylthio)l-4-methoxycarbonylmethylsydnone.

EXAMPLE 40 3-l2-(p-tert.-Butylphenylthio)ethyl]-4-carb0yxmethylsydnone.A solution consisting of 3 parts of 3-[2-(ptert.-butylphenylthio)ethyl1-4-methoxycarbonylmethylsydnone, partsof tetrahydrofuran, 30 parts of water and part by volume of concentratedsulfuric acid is heated at 35"40 under a nitrogen atmosphere for 5 days.After that time, the mixture is poured into water and extracted withbenzene. After successively washing the extracts with water andsaturated aqueous sodium bicarbonate, the basic extracts are acidifiedand extracted again with benzene. Then they are dried over anhydroussodium sulfate and evaporated to drymess, The material remaining isrecrystallized from isopropanolwater to give 3[ 2-( p-te rt.-butylphenylthio)ethyl]-4carboxymethylsydnone, melting at about l37".

EXAMPLE 4i A. N-(2-Phenoxyethyl)alanine. The procedure de tailed inExample 2A is repeated using 32 parts of B-phenoxyethylamine, 36 partsof Z-bromopropionic acid, 26 parts of potassium t butoxide and 600 partsof t-butanol, thus producing N-(2phenoxyethyl)alanine.

B. N-(2-Phenoxyethyl)N-nitrosoalanine. The procedure detailed in Example88 is repeated using 48 parts of N-(Z-phenoxyethyl)alanine, 16 parts ofsodium nitrite, 300 parts of water and 400 parts of dichlorometh ane,thus producing N-( 2-phenoxyethyl)-N- nitrosoalanine.

C. 4-Methyl3-(2 phenoxyethyl)sydnone, The procedure detailed in Example7C is repeated using 14 parts of N-(2-phenoxyethyl)-N-nitrosoalanine and210 parts of acetic anhydride, thereby affording 4-methyl-3-2-phenoxyethyllsydnone, melting at about 99-l00. That product isrepresented by the following structural formula EXAMPLE 42 A.N-[3-(p-Chlorophenylthio)-2-propyl]alanine. Substitution of 48 parts of3-(p-chlorophenylthio)-2- propylamine hydrochloride, 45 parts oft-potassium butoxide, 3] parts of Z-bromopropionic acid and 600 parts byvolume of t-butanol, in the procedure of Example 2A affords N-[3-(p-chlorophenylthio)-2- propyl]alanine.

B. N-[3-(p-Chlorophenylthio)-2-propyl]-N- nitrosoalanine. Substitutionof 14 parts of N-[3-(pchlorophenylthio)-2-propyl]alanine, 5 parts ofsodium nitrite, 200 parts of water, and 280 parts of dichloromethane inthe procedure of Example 88 affords N-[3-(p-chlorophenylthio)-2-propyl]-N-nitrosoalanine.

C. 3-[3-(p-Chlorophenylthio)-2-propyl]-4- methylsydnone. Substitution of[3 parts of N-[3-(pchlorophenylthio)-2-propyl]-N-nitrosoalanine and 150parts of acetic anhydride in the procedure of Example 7C, affords3[3-(p-chlorophenylthio)-2-propyl]-4- methylsydnone, melting at about8485.

EXAMPLE 43 A. N-[Z-(p-Bromophenylthio)ethyl]alanine. Repetition of theprocedure detailed in Example 2A while utilizing 16! parts ofZ-(p-bromophenyl)ethylamine, l34 parts of 2-bromopropionic acid, 65parts of sodium methoxide and 2800 parts by volume of t-butanol, affordsN-[2-(p bromophenylthio)ethyllalanine.

B. N-[2-(p-Bromophenylthio)ethyll-Nmitrosoalanine. Repetition of theprocedure detailed in Example 83 while utilizing 115 parts ofN-[Z-(pbromophenylthio)-ethyl]alanine, 27 parts of sodium nitrite, 1000parts of water and 1400 parts of dichloromethane affordsN-[2-(p-bromophenylthio)ethyll-N- nitrosoalanine,

C. 3-[2-(p-Bromophenylthio)ethyl]-4- methylsydnone. Repetition of theprocedure detailed in Example 7C while utilizing I05 parts ofN-[2-(pbromophenylthio)-ethylI-N-nitrosoalanine and 1000 parts of aceticanhydride affords 3-[2-(pbromophenylthio)ethyll-4-methylsydnone, meltingat about 84.585.5.

EXAMPLE 44 By substituting equivalent quantities of2-(omethylphenylthio)ethylamine. 2-(2,4,6-

trimethylphenylthio)ethylamine, Z-(o-methoxyphenylthio)ethylamine,2-(4-bromo-3-methylphenylthio)ethylamine,2'(2,3,4,5.o-pentachlorophenylthio)ethylamine and2(p-fluorophenylthio)ethylamine in the procedure of Example 2A, and ineach instance employing equivalent amounts of potassium t-butoxide and2- bromopropionic acid for the sodium methoxide and 2- bromoacetic acidused therein. there is obtained, re-

22 spectively, N-[2-(o-methylphenylthio)ethyl1alanine,N-[2-(2,4,6-trimethylphenylthio)ethyl]alanine, N-[2-(o-methoxyphenylthio)ethyl]alanine, N-]2-(4-bromo-3-methylphenylthio)ethyllalanine, N-[2-(2,3,4,5,6-pentachlorophenylthio)ethyl1alanine and N-[2-(pfluorophenylthio )ethyl]alanine.

EXAMPLE 45 Successively processing equivalent quantities of each of theabove compounds according to the procedures outlined in Examples 8B and7C affords the corresponding sydnones, 3-[2-(o-methylphenylthio)ethyl]-4-methylsydnone, melting at about 8283, 3-[2-(2-(2,4,6-trimethylphenylthio)ethyl]-4-methylsydnone,

melting at about 63-64, 3-[2-(0-methoxyphenylthio)ethyl]-4-methylsydnone, melting at about 57-59,3-[2-(4-bromo-3- methylphenylthio)ethyll-4-methylsydnone, melting atabout 77, 3-[2-(2.3,4,5,6- pentachlorophenylthio)ethyl]-4-methylsydnone,melting at about and 3-[2-(p-fluorophenylthio)ethyl]- 4-methylsydnone,melting at about 9293.

EXAMPLE 46 wherein R represents hydrogen, lower alkyl, phenyl, or bromo;Alk represents alkylene containing more than I and fewer than 5 carbons;2 represents oxygen, thio, sulfinyl, or sulfonyl; 1: represents 0 or 1;and Ar represents naphthyl, phenyl, or phenyl substituted by membersselected from less than 3 of the group consisting of lower alkyl,halogen, lower alkoxy, and nitro.

2. A compound according to claim I having the for mula wherein Rrepresents hydrogen or lower alkyl', Alk represents alkylene containingmore than 1 and fewer than 5 carbons; Z represents thio, sulfinyl orsulfonyl; .r represents 0 or 1; and Ph represents (lower alky|)phenyl,halophenyl having fewer than 3 halogens, (lower alkoxy)phenyl ornitrophenyl.

3. A compound according to claim 1 having the for mula 4. A compoundaccording to claim 1 which is 4- methyl-312-(phenylthio)ethy]]sydnone.

5. A compound according to claim 1 having the formula lower alkyl mula aogen wherein Alk represents alkylene containing more than I and fewerthan 4 carbons.

8. A compound according to claim 1 which is 3-[2-(p-chlorophenylthio)ethyl1-4-methylsydnone.

9, A compound according to claim 1 having the formula Cl ON N- CH CH S10. A compound according to claim 1 having the formula lower alkoxy 0 N(D l C NCH CH S 11. A compound according to claim 1 which is 3-[ L(p'methoxyphenylthio)ethyl]-4mcthylsydnone.

12. A compound according to claim 1 having the for mula 0 0 N O (5 l t ac N-Alk-S wherein Alk represents alkylene containing more than 1 andfewer than 5 carbons.

13. A compound according to claim 1 which is 4-methyl-3-[3-(phenylsulfinyl)propyllsydnone.

14. A compound according to claim 1 having the for mula O O W l A H C-CH CH lower alkyl 0 l S 15. A compound according to claim 1 which is3-[2- (p-tert.-butylphenylsulfinyl)ethyll-4-methylsydnone.

16. A compound according to claim i having the formula halogen 17. Acompound according to claim 1 which is 3-[2-(p-chlorophenylsulfinyl)ethyl]-4-methylsydnone.

18. A compound according to claim 1 having the formula lower alkyl 19. Acompound according to claim I which is 3-[2-(p-tert.-butylphenylsulfonyl)ethyl]-4-methylsydnone.

20. A compound according to claim 1 having the formula wherein Rrepresents hydrogen or lower alkyl, Alk rep resents alkylene containingmore than 1 and fewer than 5 carbons; 2 represents thio. sulfinyl orsulfonyl; and x represents 0 or I.

26 2]. A compound according to claim 1 having the for- 22. A compoundaccording to claim 1 which is 4- mulamethyl-3-]2-(2-naphthylthis)cthyllsydnone.

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 havingthe formula
 3. A compound according to claim 1 having the formula
 4. Acompound according to claim 1 which is4-methyl-3-(2-(phenylthio)ethyl)sydnone.
 5. A compound according toclaim 1 having the formula
 6. A compound according to claim 1 which is3-(2-(p-tert.-butylphenylthio)ethyl)-4-methylsydnone.
 7. A compoundaccording to claim 1 having the formula
 8. A compound according to claim1 which is 3-(2-(p-chlorophenylthio)ethyl)-4-methylsydnone.
 9. Acompound according to claim 1 having the formula
 10. A compoundaccording to claim 1 having the formula
 11. A compound according toclaim 1 which is 3-(2-(p-methoxyphenylthio)ethyl)-4-methylsydnone.
 12. Acompound according to claim 1 having the formula
 13. A compoundaccording to claim 1 which is4-methyl-3-(3-(phenylsulfinyl)propyl)sydnone.
 14. A compound accordingto claim 1 having the formula
 15. A compound according to claim 1 whichis 3-(2-(p-tert.-butylphenylsulfinyl)ethyl)-4-methylsydnone.
 16. Acompound according to claim 1 having the formula
 17. A compoundaccording to claim 1 which is3-(2-(p-chlorophenylsulfinyl)ethyl)-4-methylsydnone.
 18. A compoundaccording to claim 1 having the formula
 19. A compound according toclaim 1 which is3-(2-(p-tert.-butylphenylsulfonyl)ethyl)-4-methylsydnone.
 20. A compoundaccording to claim 1 having the formula
 21. A compound according toclaim 1 having the formula
 22. A compound according to claim 1 which is4-methyl-3-)2-(2-naphthylthis)ethyl) sydnone.